The unique complexity of the CYP3A4 upstream region suggests a nongenetic explanation of its expression variability

Qiu, Huan; Mathäs, Marianne; Nestler, Sebastian; Bengel, Christopher; Nem, Dieudonné; Gödtel-Armbrust, Ute; Lang, Thomas; Taudien, Stefan; Burk, Oliver; Wojnowski, Leszek

doi:10.1097/fpc.0b013e328336bbeb

Cited by 21 publications

(17 citation statements)

References 40 publications

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“…The activity of this enzyme is known to show a significant variability not only between different individuals but also within the same individual at different time points. The reason for this activity is unknown, but a recent study on the upstream regulatory region of the CYP3A4 gene suggests an extraordinary potential for interactions with exogenous and endogenous ligands of different nuclear receptors (Qiu et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Seasonal Variation in Blood Drug Concentrations and a Potential Relationship to Vitamin D

Lindh

Andersson²,

Eliasson

et al. 2011

Drug Metab Dispos

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ABSTRACT:The most important enzyme in hepatic drug metabolism is cytochrome P450 3A4. Published in vitro data indicate that vitamin D may up-regulate the expression of the CYP3A4 gene. Individual vitamin D levels are highly dependent on sunlight exposure and show great seasonal variability in northern countries. The aim of the present study was to investigate whether plasma concentrations of CYP3A4 drug substrates exhibit seasonal changes compatible with a stimulatory effect of vitamin D on drug metabolism. Three immunosuppressants (tacrolimus, sirolimus, and cyclosporine) were analyzed, because these CYP3A4 drug substrates are subject to long-term use and repeated concentration determinations. In addition, mycophenolic acid was included in the analysis as a control drug independent of CYP3A4 metabolism. Concentration-to-dose ratios were extracted from the Karolinska Therapeutic Drug Monitoring database and compared between the 3-month periods of lowest and highest vitamin D levels. Sirolimus and tacrolimus levels showed seasonal variability that was highly consistent with changes in vitamin D; for example, significantly lower drug concentrations in July to September than in January to March. As expected, no significant difference was evident for mycophenolic acid, but this result was also the case with cyclosporine, possibly due to cross-reactivity of CYP3A4-mediated metabolites with the immunoassay used for quantification. In conclusion, there is cyclic variation in blood levels of important immunosuppressants throughout the year that correlates with UV light-dependent changes in vitamin D levels. Even though a causal relationship remains to be established, it is suggested that individual differences in vitamin D may contribute to variability in drug metabolism and disposition.

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Section: Introductionmentioning

confidence: 99%

Seasonal Variation in Blood Drug Concentrations and a Potential Relationship to Vitamin D

Lindh

Andersson²,

Eliasson

et al. 2011

Drug Metab Dispos

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“…However, the co-transfection of a PXR-expressing construct had only a weak (two-fold increase) and statistically not significant effect on the activity of the proximal CYP3A4 promoter (Figure 8). We then co-transfected into these cells PXR together with the proximal CYP3A4 promoter extended by the PXR-responsive enhancer XREM present in the CYP3A4 , but not in the CYP3A5 distal promoter [34]. In this case, PXR resulted in a 13-fold increase in the luciferase activity (Figure 8).…”

Section: Resultsmentioning

confidence: 98%

“…The conservation of the primate CYP3A5 and CYP3A4 promoters is limited to their most proximal parts [34]. We investigated if these parts are sufficient to confer the previously reported differential expression of these genes in renal cells [12].…”

Section: Resultsmentioning

confidence: 99%

“…We first established a two-cell line model of the small intestine and kidney, two organs expressing CYP3A5. The LS174T cells have been repeatedly validated as a faithful model of the basal and drug-induced CYP3A expression in the small intestine [34], [47], including the induction of CYP3A5 [2]. The MDCK.2 cells exhibit many characteristics of the collecting duct cells, a principal site of CYP3A5 expression in the kidney [16], [17], [18].…”

Section: Discussionmentioning

confidence: 99%

“…Together with the proximal ER6 (Figure 2) and the far-distal constitutive liver enhancer module (CLEM), XREM represents the original scheme of CYP3A regulation by nuclear receptors such as PXR in placental mammals [34]. The need to offset the inhibitory effect of YY1 may have been the force driving both the conservation of XREM and the origin of novel PXR-responsive elements outside XREM recently described in the CYP3A4 gene lineage [34]. Conversely, the loss of XREM from the CYP3A5 gene lineage [34] is consistent with the reduced pressure to maintain XREM, conferred by the loss of the transcriptionally repressive YY1 binding site.…”

Section: Discussionmentioning

confidence: 99%

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Pregnane X Receptor and Yin Yang 1 Contribute to the Differential Tissue Expression and Induction of CYP3A5 and CYP3A4

et al. 2012

Self Cite

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The hepato-intestinal induction of the detoxifying enzymes CYP3A4 and CYP3A5 by the xenosensing pregnane X receptor (PXR) constitutes a key adaptive response to oral drugs and dietary xenobiotics. In contrast to CYP3A4, CYP3A5 is additionally expressed in several, mostly steroidogenic organs, which creates potential for induction-driven disturbances of the steroid homeostasis. Using cell lines and mice transgenic for a CYP3A5 promoter we demonstrate that the CYP3A5 expression in these organs is non-inducible and independent from PXR. Instead, it is enabled by the loss of a suppressing yin yang 1 (YY1)-binding site from the CYP3A5 promoter which occurred in haplorrhine primates. This YY1 site is conserved in CYP3A4, but its inhibitory effect can be offset by PXR acting on response elements such as XREM. Taken together, the loss of YY1 binding site from promoters of the CYP3A5 gene lineage during primate evolution may have enabled the utilization of CYP3A5 both in the adaptive hepato-intestinal response to xenobiotics and as a constitutively expressed gene in other organs. Our results thus constitute a first description of uncoupling induction from constitutive expression for a major detoxifying enzyme. They also suggest an explanation for the considerable tissue expression differences between CYP3A5 and CYP3A4.

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Human Cytochrome P450 Enzymes

Guengerich

2015

Cytochrome P450

137

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The unique complexity of the CYP3A4 upstream region suggests a nongenetic explanation of its expression variability

Abstract: Instead of gene variants, the intraindividual CYP3A4 expression variability in humans may be primarily caused by particular sensitivity of this gene to endogenous and exogenous PXR and CAR ligands conferred by the unique complexity of its upstream regulatory region.

Cited by 21 publications

References 40 publications

Seasonal Variation in Blood Drug Concentrations and a Potential Relationship to Vitamin D

Seasonal Variation in Blood Drug Concentrations and a Potential Relationship to Vitamin D

Pregnane X Receptor and Yin Yang 1 Contribute to the Differential Tissue Expression and Induction of CYP3A5 and CYP3A4

Human Cytochrome P450 Enzymes

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